TAILIEUCHUNG - Báo cáo Y học: Determinants of antagonist binding at the a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor subunit, GluR-D Role of the conserved arginine 507 and glutamate 727 residues

Previous structural andmutagenesis studies indicate that the invariant a-amino and a-carboxyl groups of glutamate receptor agonists are engaged in polar interactions with oppositely charged, conserved arginine and glutamate resi-dues in the ligand-binding domain ofa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid examine the role of these residues (R507 and E727 in the GluR-D subunit) in the discrimination between agonists and anta-gonists, we analyzed the ligand-binding properties of homomeric GluR-D and its soluble ligand-binding domain withmutations at thesepositions | Eur. J. Biochem. 269 6261-6270 2002 FEBS 2002 doi Determinants of antagonist binding at the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR-D Role of the conserved arginine 507 and glutamate 727 residues Annukka Jouppila1 Olli T. Pentikainen2 Luca Settimo2 Tommi Nyronen3 Jukka-Pekka Haapalahti1 Milla Lampinen1 David G. Mottershead1 Mark S. Johnson2 and Kari Keinanen1 1Viikki Biocenter Department of Biosciences Division of Biochemistry and Institute of Biotechnology University of Helsinki Finland 2Department of Biochemistry and Pharmacy Abo Akademi University Turku Finland 3 CSC - Scientific Computing Ltd Espoo Finland. Subdivision in Eur. J. Biochem. Neurochemistry Previous structural and mutagenesis studies indicate that the invariant a-amino and a-carboxyl groups of glutamate receptor agonists are engaged in polar interactions with oppositely charged conserved arginine and glutamate residues in the ligand-binding domain of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. To examiee the role of these residues R507 and E727 in the GluR-D subunit in the discrimination between agonists and antagonists we analyzed the ligand-binding properties of homomeric GluR-D and its soluble ligand-binding domain with mutations at these positions. Fi 1 ter- bind ing assays using 3H AMPA an agonist and 3H Ro 48-8587 a high-affinity antagonist as radioligands revealed that even a conservative mutation at R507 R507K resulted in the complete loss of both agonist and antagonist binding. In contrast a negative charge at position 727 was necessary for agonist binding whereas the isosteric mutation E727Q abolished all agonist binding but retained high-affinity binding for 3H Ro 48-8587 displaceable by 7 8-dinitroquinoxaline-2 3-dione. Competition binding studies with antagonists representing different structural classes in combination with ligand docking experiments suggest that the role of E727 is .

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